NM_014673.5:c.361A>C

Variant names:

• chr8-108455928-A-C
• NM_014673.5:c.361A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014673.5(EMC2):​c.361A>C​(p.Thr121Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EMC2 NM_014673.5 missense, splice_region
• Scores: Splicing: ADA: 0.9087
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.95
• Publications: 0 publications found

Genes affected

EMC2 (HGNC:28963): (ER membrane protein complex subunit 2) Contributes to membrane insertase activity. Involved in protein insertion into ER membrane by stop-transfer membrane-anchor sequence and tail-anchored membrane protein insertion into ER membrane. Located in endoplasmic reticulum membrane. Is extrinsic component of endoplasmic reticulum membrane. Part of EMC complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014673.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC2	NM_014673.5	MANE Select	c.361A>C	p.Thr121Pro	missense splice_region	Exon 5 of 11	NP_055488.1	Q15006
	EMC2	NM_001329493.2		c.388A>C	p.Thr130Pro	missense splice_region	Exon 5 of 11	NP_001316422.1
	EMC2	NM_001329495.2		c.364A>C	p.Thr122Pro	missense splice_region	Exon 6 of 12	NP_001316424.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMC2	ENST00000220853.8	TSL:1 MANE Select	c.361A>C	p.Thr121Pro	missense splice_region	Exon 5 of 11	ENSP00000220853.3	Q15006
	EMC2	ENST00000890427.1		c.388A>C	p.Thr130Pro	missense splice_region	Exon 5 of 11	ENSP00000560486.1
	EMC2	ENST00000890429.1		c.385A>C	p.Thr129Pro	missense splice_region	Exon 5 of 11	ENSP00000560488.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 16

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.69	N
PhyloP100		8.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.46
Sift	Benign	0.077	T
Sift4G	Benign	0.18	T
Polyphen		0.92	P
Vest4		0.60
MutPred		0.36		Gain of glycosylation at T121 (P = 0.0269)
MVP		0.88
MPC		0.34
ClinPred		0.84	D
GERP RS		5.6
Varity_R		0.77
gMVP		0.78
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Benign	0.72
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr8-109468157;